Bone morphogenetic proteins and zebrafish inner ear development.

This thesis describes the mRNA expression patterns of the Bone Morphogenetic Proteins (BMPs), downstream members of the BMP signal pathway, BMP antagonists and candidate target genes in the developing inner ear of wild type zebrafish. The crista Bmp expression pattern is conserved between four vertebrate species. However, unlike in chick, mouse and Xenopus laevis none of the hmps examined are macula markers in zebrafish. This thesis identifies sources of Bmp signalling (the cristae, the endolymphatic duct (ED) and the semicircular canals (SCC)) and possible sites of Bmp action (the cristae, posterior macula, SCC and the mesenchyme around the ED). It also provides the first description of the early stages of ED development, a structure only recently described at later stages in the zebrafish (8dpf), and two mRNA markers of this structure (bmp4 and dachA). In analysis of zebrafish mutants with defective cristae, the presence of cristae correlated with the expression of the hmps and msxc, a putative Bmp target. This suggests the Bmps are required to form cristae and express msxc. Gain and loss of function studies have also supported a role for the Bmps in the development of the posterior macula and SCc. Ectopic hBMP4 protein was applied to the otic vesicle via protein-coated beads. This inhibited the development of the posterior macula and SCC. However, these hBMP4 beads were not sufficient to induce the expression of ectopic msxc, generate ectopic cristae or rescue crista development in mutants. Beads coated in a BMP antagonist did not affect the development of endogenous cristae or the expression of endogenous msxc. Rescued swirl (bmp2b) mutant adult zebrafish exhibit a balance defect. Early stages of inner ear development in rescued embryos were found to progress normally up until 7dpf. However, it is not clear when the rescuing mRNA or protein degrades, and work done by others in the lab has shown that Bmp2b is required at later stages to form adult SCc. The ectopic hBMP4 experiments suggest that moderating levels of Bmp signalling may be required for normal development of the SCC at early stages

Eliciting the child's voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative: Reeve et al.

Adverse event (AE) reporting in oncology trials is required, but current practice does not directly integrate the child’s voice. The Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is being developed to assess symptomatic AEs via child/adolescent self-report or proxy-report. This qualitative study evaluates the child’s/adolescent’s understanding and ability to provide valid responses to the PRO-CTCAE to inform questionnaire refinements and confirm content validity

A Late Role for bmp2b in the Morphogenesis of Semicircular Canal Ducts in the Zebrafish Inner Ear

BACKGROUND:The Bone Morphogenetic Protein (BMP) genes bmp2 and bmp4 are expressed in highly conserved patterns in the developing vertebrate inner ear. It has, however, proved difficult to elucidate the function of BMPs during ear development as mutations in these genes cause early embryonic lethality. Previous studies using conditional approaches in mouse and chicken have shown that Bmp4 has a role in semicircular canal and crista development, but there is currently no direct evidence for the role of Bmp2 in the developing inner ear. METHODOLOGY/PRINCIPAL FINDINGS:We have used an RNA rescue strategy to test the role of bmp2b in the zebrafish inner ear directly. Injection of bmp2b or smad5 mRNA into homozygous mutant swirl (bmp2b(-/-)) embryos rescues the early patterning defects in these mutants and the fish survive to adulthood. As injected RNA will only last, at most, for the first few days of embryogenesis, all later development occurs in the absence of bmp2b function. Although rescued swirl adult fish are viable, they have balance defects suggestive of vestibular dysfunction. Analysis of the inner ears of these fish reveals a total absence of semicircular canal ducts, structures involved in the detection of angular motion. All other regions of the ear, including the ampullae and cristae, are present and appear normal. Early stages of otic development in rescued swirl embryos are also normal. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate a critical late role for bmp2b in the morphogenesis of semicircular canals in the zebrafish inner ear. This is the first demonstration of a developmental role for any gene during post-embryonic stages of otic morphogenesis in the zebrafish. Despite differences in the early stages of semicircular canal formation between zebrafish and amniotes, the role of Bmp2 in semicircular canal duct outgrowth is likely to be conserved between different vertebrate species

The Power of Massage in Children with Cancer—How Can We Do Effective Research?

Children with cancer experience multiple troubling symptoms. Massage offers a safe, non-pharmacological approach to address these symptoms. Numerous studies of massage in children and adults with cancer have been performed, yet most are unable to demonstrate significant benefit. This review aims to summarize what we know about the role of massage and sets goals and challenges for future massage research. This paper descriptively reviews the existing literature available in PubMed (both prior reviews and select papers) and the holes in prior research studies. Prior research on massage has been limited by small sample size/insufficient power, inappropriate outcome measures or timing, heterogeneous patient populations, inconsistent intervention techniques, and other design flaws. Based on the findings and limitations of previous work, numerous suggestions are made for future studies to increase the potency of findings, including thoughts about appropriate dosing, control groups, type of intervention, outcome measures, patient selection, feasibility, and statistics

Nurse-Led Programs to Facilitate Enrollment to Children\u27s Oncology Group Cancer Control Trials.

The progress made over the past 50 years in disease-directed clinical trials has significantly increased cure rates for children and adolescents with cancer. The Children’s Oncology Group (COG) is now conducting more studies that emphasize improving quality of life for young people with cancer. These types of clinical trials are classified as cancer control (CCL) studies by the National Cancer Institute and require different resources and approaches to facilitate adequate accrual and implementation at COG institutions. Several COG institutions that had previously experienced problems with low accruals to CCL trials have successfully implemented local nursing leadership for these types of studies. Successful models of nurses as institutional leaders and “champions” of CCL trials are described

Circadian Activity Rhythms and Fatigue of Adolescent Cancer Survivors and Healthy Controls: A Pilot Study.

STUDY OBJECTIVES: The primary objective of this study was to compare circadian activity rhythms (CARs) of adolescents within 5 years of completing cancer treatment (survivors) with that of healthy adolescent controls. Secondary objectives were to explore differences in the relationship of CARs and fatigue between survivors and controls and between early survivors (<12 months posttreatment) and late survivors (≥12 months posttreatment). METHODS: Twenty-nine survivors and 30 controls, aged 13–18 years, participated in this prospective, descriptive pilot study. Adolescents and their parents completed a baseline measure of adolescents’ fatigue. Adolescents wore a wrist actigraph continuously for 7 days and concurrently kept a sleep diary. Activity data recorded by actigraphy were fitted to an extended cosine model to calculate six CAR variables: acrophase, amplitude, midline estimating statistic of rhythm (MESOR), up-MESOR, down-MESOR, and F-statistic. Linear mixed models explored the relationship between CARs and fatigue. RESULTS: There were no group differences on CAR or fatigue measures. Among survivors, earlier down-MESOR was associated with greater parent-reported fatigue (P = .020), and earlier acrophase (P = .023) and up-MESOR (P = .025) were associated with greater adolescent-reported fatigue. Significant CAR-by-time posttreatment interaction effects were found on fatigue between early and late survivors. Among controls, greater parent-reported fatigue was associated with greater MESOR (P = .0495). CONCLUSIONS: Survivors within the first 5 years posttreatment were similar to controls in CARs and fatigue, suggesting robust recovery of circadian rhythms posttreatment. Different CAR characteristics were associated with fatigue in survivors and controls. Time posttreatment influenced the relationship between CARs and fatigue for survivors, with significant effects only for early survivors. CITATION: Rogers VE, Mobray C, Zhu S, et al. Circadian activity rhythms and fatigue of adolescent cancer survivors and healthy controls: a pilot study. J Clin Sleep Med. 2020;16(7):1141–1147